FR3000064A1 - SPIROISOXAZOLINE-LIKE COMPOUNDS WITH POTENTIALIZING ACTIVITY OF AN ANTIBIOTIC COMPOSITION AND PHARMACEUTICAL PRODUCT COMPRISING SUCH COMPOUNDS - Google Patents

Abstract

The present invention relates to a spiroisoxazoline compound of general formula (I): The present invention also relates to the use of this compound. as a medicament, particularly in the treatment of bacterial and mycobacterial infections such as tuberculosis in combination with an antibiotic active against bacteria and / or mycobacteria, said compound potentiating the activity of said antibiotic.

Description

The present invention relates to spiroisoxazoline compounds for use in the treatment of bacterial and mycobacterial infections such as, for example, tuberculosis, leprosy and atypical mycobacterial infections.

The present invention also relates to novel compounds useful as a medicament in particular as a medicament for the treatment of bacterial and mycobacterial infections such as, for example, tuberculosis, leprosy and atypical mycobacterial infections.

The present invention also relates to pharmaceutical compositions comprising, as active principle, at least one of the abovementioned compounds and optionally an antibiotic active against bacteria and / or mycobacteria, in particular an antibiotic activatable by the EthA route.

The present invention also relates to products (kits) containing at least one of the abovementioned compounds and at least one antibiotic active against bacteria and / or mycobacteria, in particular an antibiotic activatable according to the EthA route as combination products for simultaneous use. , separated or spread over time in general antituberculous, antilepromatous or antimycobacterial therapy. Tuberculosis kills 2 million people each year worldwide. The AIDS epidemic and the emergence of multi-antibiotic resistant strains help compound the impact of this disease, considered by the World Health Organization to be responsible for an increasingly dangerous global epidemic and as an emergency health care at the global level.

An increasing number of strains of Mycobacterium tuberculosis is today characterized by a multi-resistance to first-line antibiotics such as isoniazid (INH) and rifampicin (RIF). These antibiotics must then be replaced by second-line antibiotics such as ethionamide (ETH) to which the strains are not resistant but which have the disadvantage of having a low therapeutic index (the therapeutic index of an active ingredient is the ratio from the therapeutic dose to the toxic dose). A strategy of increasing the activity of ethionamide (ETH) by associating it with a particular compound has already been contemplated. Indeed, ETH is a prodrug that is transformed in vivo into a therapeutically active form by the enzyme EthA (see the article "Activation of the prodrug ethionamide is regulated in mycobacteria" 2000 Journal of Biological Chemistry). The resistances observed at ETH come from the fact that the transcriptional repressor EthR of M. tuberculosis controls the expression of the enzyme EthA and limits the transformation of ETH into a therapeutically active substance. An object of the present invention is to provide novel compounds capable of potentiating the activity of antibiotics active especially against mycobacteria, in particular antibiotics active against mycobacteria and activatable by the EthA route, such as, for example, all antibiotics. of the family of thioamides and in particular, ethionamide and prothionamide. Another object of the present invention is to provide compounds as mentioned above which, in combination with an antibiotic active against bacteria and / or mycobacteria, can be used, in particular an antibiotic active against mycobacteria and activatable by the route of the EthA. obtain at an equal antibiotic dose a better efficacy or that make it possible to reduce the dose of antibiotic mentioned above to obtain a given efficiency.

Another object of the present invention is to provide compounds as mentioned above which are simple and inexpensive to produce. Another object of the present invention is to provide compounds as mentioned above that are satisfactorily soluble in a biological fluid.

Another object of the present invention is to provide compounds as mentioned above which are likely to be active, especially orally and / or which generate fewer side effects. To achieve at least one of the above objectives, the present invention therefore provides compounds of general formula (I): wherein R 2 (I) wherein m = 0 or 1; n = 0 or 1; R 1 represents a group chosen from the following groups: linear or branched C 1 -C 5 alkyl chains, linear or branched and substituted C 1 -C 4 alkyl chains, in particular substituted by at least one fluorine (F) atom, in particular linear or branched C 1 -C 3 alkyl chains substituted with at least one fluorine atom (F) or with a saturated or unsaturated C 3 -C 6 cyclic group; saturated or unsaturated C3-C6 cyclic groups and CN, CH2CN, CH2N3 groups. R2 is chosen from the following groups: phenyl, optionally substituted benzyl, in particular benzyl substituted by a Cl or F atom, naphatalenyl, substituted phenyl, in particular phenyl substituted by at least one linear or branched C1-C4 alkyl chain, phenyl substituted by at least one linear or branched and substituted C 1 -C 4 alkyl chain, in particular substituted by at least one fluorine (F) atom, phenyl substituted with at least one group chosen from OCH 3, OCF 3, Cl, F, CH 3 SO 2 or CF 3, a phenyl group of which two consecutive carbon atoms are substituted with the same group O-CH 2 -O, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, the saturated or unsaturated 5 or 6-membered heterocycles containing at least one atom in the ring chosen from S, N and O, in particular aromatic heterocyles with 5 or 6 vertices comprising at least one atom in the ring chosen from S, N and O. According to the invention n m and n may be equal or different from each other. Advantageously, m = n = 1. Such compounds are found to be particularly active in combination with ethionamide on mycobacteria, particularly on M. tube rculosis. R1 may represent a group chosen from the following groups: -CH2CF3, -CF2CF3, - (CH2) 2CF3, -CH2-isopropyl, cyclopropyl, cyclobutyl, -cyclopentyl, cyclopentenyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2 cyclopentyl, optionally substituted phenyl, in particular phenyl substituted by chlorine (Cl) or fluorine (F), optionally substituted benzyl, in particular benzyl substituted by Cl or F, O-phenyl and thiophenyl. The substituted R1 groups mentioned above may be monosubstituted or plurisubstituted. According to one embodiment, the aforementioned 5 groups are monosubstituted; the phenyl or benzyl group is then substituted only by a Cl atom or an F atom. The position of this Cl or F atom is not limited according to the invention, whether the phenyl or benzyl group is monosubstituted or plurisubstituted. Thus, the Cl or F atom may be in the ortho, meta or para position with respect to the carbon of the benzene ring linked to the remainder of the molecule of general formula (I) or with respect to the carbon of the benzene ring bonded to the bounded CH 2 group. to the rest of the molecule of general formula (I), in the case of a benzyl group. Advantageously, R1 is chosen from CH2CF3 and - (CH2) 2CF3. These two radicals provide the compounds of the invention with improved efficiency. It seems that, especially when R1 = CH2CF3, the compound of the invention is particularly effective for increasing the activity of ethionamide on mycobacteria and in particular on M. tube rculosis. According to one embodiment, R2 is chosen from the following groups: phenyl, ortho-substituted phenyl groups by OCH3, OCF3, Cl, F or CF3, in particular substituted by ortho OCH3 or Cl. Advantageously, the phenyl groups are monosubstituted ortho by a radical selected from OCH3, OCF3, Cl, F or CF3, in particular ortho monosubstituted by OCH3 or Cl. Such radicals improve the potentiating activity of the ethionamide of the compounds of the invention. The ortho position of the substituent enhances the potentiating activity of the ethionamide of the compounds of the invention. According to another embodiment, R 2 is chosen from aromatic heterocyclic rings with 5 or 6 atoms, of which at least one atom 5 adjacent to the heterocycle atom linked in alpha position with respect to 0 N of the nitrogen of the ring of the compound of general formula (I) of the invention is a sulfur atom, an oxygen atom or a nitrogen atom. According to the invention, the heterocycles with 5 or 6 atoms may therefore comprise two atoms chosen from the S, N and O atoms. In this case, the two atoms chosen from S, N and O may be located on both sides. Another is the heterocycle atom linked to the carbon ring at the alpha of the ring nitrogen in formula (I) and directly adjacent thereto. The heterocycle atom bonded to the aforementioned ring is preferably a carbon atom. Advantageously, R2 is chosen from the following groups. Such compounds are particularly effective in combination with ethionamide for controlling mycobacteria, in particular M. tuberculosis. According to another embodiment, R2 is chosen from the following groups: N 1 1 \ N \ 1 N and The compound of the invention is advantageously chosen from the following compounds: s \; The present invention also relates to the abovementioned compounds for their use as medicaments, in particular for their use in the treatment of the above-mentioned compounds. the treatment of bacterial and mycobacterial infections, particularly in the treatment of tuberculosis, leprosy or atypical mycobacteriosis. The present invention also relates to a pharmaceutical composition comprising, as active principle, at least one compound of general formula (I) as mentioned above and a pharmaceutically acceptable excipient.

Within the pharmaceutical compositions in accordance with the invention, the compound (s) used as active ingredient (s) may be used in an amount that makes it possible to administer unit doses of between 0.3 mg and 1 g. about. Within the pharmaceutical compositions in accordance with the invention and when they are present, the antibiotic (s) activatable by the enzymatic route of the EthA are advantageously used in an amount allowing the administration of unit doses equal to or less than the doses usually recommended by WHO (WHO, Treatment of tuberculosis: Guidelines for National Programs, 2003, WHO / CDS / TB2003.313.), national or non-governmental health organizations, or the relevant pharmaceutical laboratories . Those skilled in the art are able to choose one or more pharmaceutically acceptable excipients depending on the route of administration of the pharmaceutical composition. Of course, those skilled in the art will take care on this occasion that the excipient or excipients used are compatible with the intrinsic properties attached to the composition according to the present invention. In addition, the form of the drug or pharmaceutical composition (e.g., solution, suspension, emulsion, tablets, capsules, suppositories, etc.) will depend on the chosen route of administration. Thus, within the meaning of the present invention, the drug or the pharmaceutical composition can be administered by any appropriate route, for example by the oral, anal, local (topical, for example), systemic, intravenous, intramuscular or mucosal, or by using a patch, or in the form encapsulated in, or immobilized on, liposomes, microparticles, microcapsules, associated with nanoparticles and the like. Mention may be made, by way of non-limiting examples of excipients suitable for oral administration, talc, lactose, starch and its derivatives, cellulose and its derivatives, polyethylene glycols, acid polymers acrylic, gelatin, magnesium stearate, animal, vegetable or synthetic fats, paraffin derivatives, glycols, stabilizers, preservatives, anti-oxidants, wetting agents, anti-caking agents, dispersants , emulsifiers, taste modifying agents, penetration agents, solubilization agents, etc. The techniques of formulation and administration of drugs and pharmaceutical compositions are well known in the art here considered, the skilled person including the latest edition of Remington's Pharmaceutical Sciences.

The present invention also relates to the use of at least one compound according to the invention for the manufacture of a medicament for the prevention and / or treatment of bacterial infections, preferably mycobacterial, and particularly tuberculosis , leprosy or atypical mycobacteriosis. Advantageously, the pharmaceutical composition further comprises, as active ingredient, at least one antibiotic active against bacteria and / or mycobacteria, chosen in particular from the antibiotics activatable by the enzymatic pathway of EthA, in particular from ethionamide, prothionamide. , isoxyl and thiacetazone which are examples of antibiotics activatable by the EthA route. The present invention is nevertheless not limited to these antibiotics. The present invention also relates to a kit or product containing at least one compound of formula (I) and at least one antibiotic active against bacteria and / or mycobacteria chosen, in particular, from the antibiotics activatable by the enzymatic pathway of the EthA, such as combination products for simultaneous, separate or time-course use in general anti-tuberculosis, anti-lepromatous or anti-mycobacterial therapy.

DEFINITIONS For the purpose of the present invention, the thiophenyl group is defined as a cyclic group comprising 4 carbon atoms and a sulfur atom. When it is not specified that a group is substituted, it is not substituted within the meaning of the present invention.

When the position of the substituent is not specified, the term substituted phenyl relates to any phenyl group of which at least one hydrogen atom is replaced by a group or an atom as indicated. Preferably, for R 2, the phenyl group is monosubstituted, preferably monosubstituted with an OCH 3 group, a chlorine atom or a fluorine atom. It can nevertheless comprise at least two substituents. The ortho position of the phenyl substituted substituent refers to the carbon atom of the phenyl moiety which is bonded to the α, N N carbon atom in the alpha position relative to the ring nitrogen of the compounds of the invention. Heterocycles with 5 or 6 atoms can be saturated or unsaturated. They may include one or more double bonds. They can also be aromatic rings. Thus, within the meaning of the present invention, the terms aromatic heterocycles with 5 or 6 vertices comprising at least one atom chosen from N, O and S in the ring include, in particular, aromatic heterocycles with 5 or 6 vertices comprising at least one atom. of nitrogen in the ring and only one or more N atoms as a heteroatom in the ring, aromatic heterocyls with 5 or 6 vertices, in particular at 5 vertices, having at least one atom 0 in the ring and only one or 0 atoms as heteroatom (s) in the ring, 5- or 6-membered aromatic heterocyls having at least one S atom in the ring and only one or more S atoms as heteroatom (s) in the ring aromatic heterocyls with 5 or 6 vertices, in particular at 5 vertices, comprising at least one nitrogen atom in the ring and / or at least one O or S atom in the ring as heteroatoms, In particular, aromatic heterocycles at 5 or 6 vertices involve two different or identical heteroatoms chosen from S, N and O are part of the aromatic heterocycles with 5 or 6 vertices according to the invention. Atypical mycobacterioses are defined here as being mycobacterioses caused by at least one mycobacterium other than M. Tuberculinum and in particular mycobacteriosis involving M. Kansasii.

For the purposes of the present invention, the term "treatment" refers to the curative treatment and / or the prophylactic treatment of the aforementioned infections. The term "treatment" includes any improvement in the patient's condition, particularly any decrease in the amount of bacteria present in at least one site of infection of the patient.

Within the meaning of the present invention, an antibiotic activatable by the EthA route is defined as any substance which, at least in vitro, reacts with the enzyme EthA to produce a substance having antibiotic properties. Those skilled in the art are able to determine if an antibiotic is activatable by way of the EthA, for example, by applying the method described in the following publication: "Activation of the prodrug ethionamide is regulated in mycobacteria" 2000 Journal of Biological Chemistry. For the purpose of the present invention, an antibiotic active against bacteria and / or mycobacteria is defined as any agent capable of limiting or reducing at least in vitro the proliferation of a bacterium and / or a mycobacterium, in particular M. tuberculosis. An agent capable of destroying, at least in vitro, a mycobacterium, in particular M. tuberculosis, is also an antibiotic active against mycobacteria, within the meaning of the present invention. Among the antibiotics active against mycobacteria and activatable by the EthA route, mention may be made of ethionamide, prothionamide, isoxyl, thiacetazone and mixtures of at least two of these antibiotics. The antibiotic in the sense of the present invention may also be an antibiotic activatable by another bioactivation pathway than that mentioned above.

EXPERIMENTAL PART SYNTHESES The 1H and 13C NMR spectra were made at room temperature on a BrukerTM DPX 300 device at 300 MHz. The chemical shifts are indicated in part per million (ppm). Assignments were performed using the one-dimensional (1D) 1H and 13C or two-dimensional (2D) experiments HSQC and COZY. The mass spectra were performed on an LCMS-MS equipped with a triple quadrupole system (Varian 1200ws) or on a LCMS Waters Alliance Micromass ZQ 2000. Commercial reagents and solvents were used without further purification. 1 (n = 1 and m = 1) 2 (n = 0 and m = 1) 3 (n = 0 and m = 0) a) tBuOK, Etp, Ph3 (CH3) P +, I- Figure 1: Synthesis scheme intermediates 1 to 3.

Synthesis of Intermediates 1, 2 and 3. Potassium tert-butoxide (1.5 mmol) is added to the suspension under argon, triphenylmethylphosphonium iodide (1.5 mmol) in anhydrous ether (2.0 mL). The mixture is refluxed for 1 h and then turns yellow. The ketone compound is then added in portions. After stirring for 30 minutes at room temperature, TLC analysis indicates that the reaction is complete. The reaction medium is then hydrolysed with distilled water (1 mL) and extracted twice with ether. The combined organic phases are dried over MgSO 4 and concentrated to dryness. The residue obtained is purified on a column of silica gel (eluent cyclohexane / ethyl acetate) to give the expected product as a colorless oil. 1-N-Boc-4-methylenepiperidine (1). NMR 1H (CDCl 3, 300 MHz) δ (MPm) 1.47 (s, 9H, CH 3 Boc), 2.18 (t, 4H, J = 5.9 Hz, CH 2), 3.42 (t, 4H, J = 5.8 Hz, CH 2 N) , 4.74 (s, 2H, = CH2). 70% yield. [(M-tBu), Hr 142.1. Purity> 95%. 1-N-Boc-3-methyleneazetidine (2). NMR 1H (CDCl 3, 300 MHz) δ (PPm) 1.46 (s, 9H CH 3 Boc), 4.49 (t, 4H, J = 2.7 Hz, CH 2), 4.99 (q, 2H, J = 2.4 Hz, CH 2). 69% yield. [(M-tBu), H] 114.3. Purity> 95%. 1-N-Boc-3-methylenepyrrolidine (3). NMR 1H (CDCl 3, 300 MHz) (ppm) 1.48 (s, 9H, CH 3 Boc), 2.55 (t, 2H, J = 7.2 Hz, CH 2), 3.48 (m, 2H, CH 2), 3.93 (m, 2H, CH2), 4.98 (m, 2H, = CH2). 83% yield. [(MtBu), H] 128.1. Purity> 95%. Synthesis Scheme of Compounds 4, 5 and 10 (c) + CFICH2) 2COOH NBoc CF, a) H step 1 4 r \ --- CF step 3 c) + CFICH,), COOH N-0 NBoc number step 2 8th Synthetic scheme of the compounds 6 to 9 step 3 CF, 16 N -OH N.OH d) RHR CI + step 2 '6a-7a 6b-7b 1 e) step 2 "6c-7c 6-9 Scheme for the synthesis of the compounds 11 to 59 b) step 2 8c-29c HO .. 0) 1 .4 RH step 1 RH 8a-29a 8b-29b Operating conditions: (a) NH2OH.HCl, CH2Cl2, pyridine, RT; (b) NaCl3 13% , CH2Cl2, 0 ° C to RT, (c) (i) HCl (4M) in 1,4-dioxane, (ii) R'-CO2H, HOBt, EDCI.HCl, DIEA, DMF, (d) NCS, DMF , RT, (e) 1-N-Boc-4-methylenepiperidine, Et3N, THF, RT; ei) HCl (4M) in 1,4-dioxane, (ii) CF3 (CH2) 2-CO2H, HOBt, EDCI HCl, DIEA, DMF Step 1: Oxim synthesis: The hydroxylamine hydrochloride (1 mmol) is added to the solution of aldehyde (1 mmol) in dichloromethane (860.1%) and pyridine ( The mixture is then stirred at room temperature The progress and the end of the reaction are monitored by chromatogra Thin film (TLC). Dichloromethane is then added and the organic phase is washed with distilled water, dried over MgSO4 and concentrated to dryness. The oxime thus obtained is used without the need for further purification. Step 2: Procedure for synthesis of intermediates 8e to 29c. The sodium hypochlorite solution (13% chlorine solution, 3.4 mL) is added to the solution of oxime (1 mmol) and alkene 1, 2 or 3 (0.8 mmol) in CH 2 Cl 2, lowered to 0 °. C. The mixture is stirred at room temperature until the reaction is complete. The two phases are separated and the organic phase is then successively washed with 1 N HCl (2 times), saturated NaHCO 3 solution and brine before being evaporated under reduced pressure. If necessary, the spiroisoxazoline derivative obtained is purified by preparative HPLC or flash chromatography (eluent cyclohexane / ethyl acetate). Step 2 'and 2 ": Procedure for Synthesis of Derivatives 6b-6c and 7b-7c N-Chlorosuccinimide (1 mmol) is added to the solution of oxime (1 mmol) in DMF (1.9 ml). After stirring at room temperature for 1 hour (the LC / MS control indicates the end of the reaction), the DMF is evaporated off under reduced pressure, the residue obtained is taken up in CH 2 Cl 2 and then washed twice with brine The organic phase is dried over MgSO 4 and concentrated to dryness The solution of triethylamine (2 mmol) in THF (32 ml) is added dropwise over 4 h to the solution of chloro-oxime and 1 g. -N-Boc-4-methylene-piperidine (1.3 mmol) in THF (32 mL) The reaction mixture is stirred at room temperature The triethylamine hydrochloride thus formed is removed by filtration and the THF is evaporated under reduced pressure. The residue obtained is taken up in dichloromethane and is washed successively with a 1N HCl solution. The organic phase is then dried over MgSO 4 and concentrated to dryness. The residue collected is purified on a column of silica gel (eluent (CH 2 Cl 2 / EtOAc).) Step 3: deprotection of the N-Boc group The solution of 4N HCl in dioxane (2.2 ml) is added to the solution of N- Boc-amine (1 mmol) in dioxane (4.4 mL) The reaction mixture is stirred at room temperature After the reaction is complete (monitored by TLC), the precipitate formed is filtered off on sintered glass and used without further purification in the reaction medium. coupling step.

Coupling with carboxylic acids: The solution of carboxylic acid (1.5 mmol), EDCI.HCl (1.5 mmol), HOBt (0.5 mmol) and diisopropylethylamine (4 mmol) in DMF is stirred at room temperature during 15 minutes. Spiroisoxazoline hydrochloride (1 mmol) is then added thereto. The reaction is complete after 2 hours of stirring (followed by LC / MS), the solvent is evaporated under reduced pressure. The residue obtained is taken up in dichloromethane and washed successively with 1N HCl (twice), a saturated solution of NaHCO 3 and brine. The organic phase is then dried over MgSO 4 and concentrated to dryness. The compound is then purified by preparative HPLC. Evaluation of the Activity of the Compounds The Cellular Potentiation Test for Ethionamide The test used makes it possible to verify that these compounds are capable of potentiating the bactericidal activity of ethionamide on macrophages infected with M. tuberculosis. This test is a test of "High Content Screening" (HCS) or screening with dense content. The HCS tests are carried out on cell cultures that make it possible to study certain phenotypic characters of a microorganism (bacterium for example) in a given environment. The phenotypic changes observed can range from the increase (or decrease) in the production of certain labeled proteins to the modification of the morphology of the microorganism studied. The method is described in the following publication: "Ethionamide Boosters: Synthesis, Biological Activity, and Structure-Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors" 2011 Journal of Medicinal Chemistry.

The purpose of this test is to determine the ligand concentration necessary to potentiate ten times the activity of ethionamide (ETH). To measure the ligand concentration necessary to potentiate the activity of ETH ten times, a constant concentration of ethionamide (04 g / ml corresponding to the Me 'of its CMI99) is used. By varying the ligand concentration one can determine the concentration necessary to inhibit 50% of the bacterial growth, that is to say the concentration necessary to potentiate ten times the activity of ethionamide. This concentration will be noted EC50. Measurement of the solubility 401.1L of a 10mM solution in the DMSO of the sample is added to 1.96mL of MeOH or PBS at pH 7.4. The samples are then stirred for 24h at RT, centrifuged for 5 min and then filtered through filters of size 0.45, tm. 20μl of each solution is then added to 180e MeOH and analyzed by LC-MS. Solubility is determined as the area ratio of the PBS / MeOH mass signals. BIOLOGICAL ACTIVITIES MEASURED Table I below groups together the formulas of the compounds of the invention tested as well as the EC50 values measured experimentally according to the abovementioned protocol.

TABLE 1 NMR compound [MH] + EC 50 (BDM R 44636 1H (CD2Cl2, 300 MHz): δ (ppm) 2.22 (m, 1H), 2.52 (m, 5H), 3.48 (m, 2H), 3.61-3.98 (m, 4H), 7.47 (m, 3H), 7.70 (m, 2H) 327 0.53 326.32 g / mol 13C (CD2Cl2, 75 MHz): δ (ppm) 26.6 and 27.1 (q, J = 2.9 Hz), 29.0 (q, J = 29.5Hz), 35.6, 37.2, 41.2 and 41.6, 44.9, 45.5, 55.7, 56.5, 89.7 and 91.2, 126.5, 128.7, 129.1, 130.3, 127.6 (q, J = 271.1Hz), 156.5 and 156.6, 167.9 and 168.2.19F (CD2Cl2, 282 MHz): 8 (ppm) -67.00, -66.98.4H (CD2Cl2, 300 MHz): BDM_44635 312.29 g / mol at (ppm) 2.26-2.56 (m, 4H) , 3.65 (s, 2H), 4.21 and 4.34 (2d, 2H, J = 11.1 and 10.5Hz), 4.32 and 4.50 (2d, 2H, J = 9.3 and 9.3Hz), 7.46 (m, 3H), 7.68 (m , 13C (CD2Cl2, 75 MHz): 313 0.11 (ppm) 24.3 (q, J = 3.1Hz), 28.8 (q, J = 28.4Hz), 44.5, 61.5, 63.7, 80.2, 126.6, 128.8, 130.5, 127.1 (q, J = 279.5 Hz), 156.8, 169.1.19F (CD2Cl2, 282 MHz): δ (ppm) -37.12.6 BDM_41774 1H (CDCl3, 300 MHz): δ (ppm) 1.69 (m, 2H) ), 1.94 (m, 2H), 2.46 (m, 4H), 3.12 (s, 2H), 3.24 (m, 1H), 3.52 (m, 2H), 4.26 (m, 1H); , 7.04 (q, 1H, J = 5.1 and 3.6Hz), 7.16 (dd, 1H, J = 3.6 and 1.1Hz), 7.38 (dd, 1H, J = 5.1 and 1.1Hz). 347 0.03 346.37 g / mol N-0 BDM_41776 347.36 g / mol 7 if N -CI (CDCl3, 300 MHz): δ (ppm) 1.72 (m, 2H), 1.95 (m, 2H), 2.45 (m, 4H) , 3.29 (s, 2H), 3.33 (m, 1H), 3.58 (m, 2H), 4.15 (m, 1H), 7.41 (d, 1H, J = 3.2Hz), 7.86 (d, 1H, J = 3.2). Hz). 13C (CDCl 3, 75MHz): δ (ppm) 25.9, 29.6 (q, J = 29.1Hz), 35.4, 36.2, 37.9, 39.0, 45.2, 85.7, 121.3, 127.1 (q, J = 274.0Hz), 143.5, 153.8, 157.7, 168.0. 348 0.04 1H (CD2Cl2, 300 MHz): BDM_44783 (ppm) 0.91 (d, 6H, J = 6.6Hz), 1.40-1.58 (m, 3H), 1.71 (m, 2H), 1.91 (m, 2H), 3.12 (s, 2H), 321 0.13 3.35 (m, 1H), 3.58 (m, 2H), 4.04 (m, 1H), 7.07 (m, 2H), 7.17 (m, 2H), 7.40 (m, 2H) . BDM_44780 1H (CDCl3, 300 MHz): δ (ppm) 1.79 (m, 2H), 1.90 (m, 4H), 2.16 (m, 2H), 2.42 (t, 2H, J = 7.2Hz), 3.29 (s, 2H), 3.33 (m, 1H), 3.58 (m, 2H), 4.03 (m, 1H), 7.45 (d, 1H, J = 3.2Hz), 7.86 (d, 1H, J = 3.2 Hz). 362 0.07 1H (CD2Cl2, 300 MHz): BDM41420 (ppm) 1.36-1.88 (m, 2H), 1.90-2.04 (m, 2H), 2.45-2.61 (m, 4H), 3.16 (s, 2H), 3.42 (m, 1H), 3.56 (m, 2H), 4.18 (m, 1H), 7.47 (m, 3H), 7.70 (m, 2H). 341 0.02 340.35 g / mol 13C (CD2Cl2, 75 MHz): 5 (ppm) 25.8, 29.5 (q, J = 39.1Hz), 35.5 and 36.2, 39.4 and 42.6, 45.3, 84.1, 126.5, 128.7 and 130.0, 127.6 ( q, J = 275.3 Hz), 156.4, 167.8. N-O 1H (CDCl 3, 300 MHz): BDM 41781 354.38 g / mol (ppm) 1.69 (m, 2H), 1.94 (m, 2H), 2.38 (s, 3H), 2.45 (m, 4H), 3.10 ( s, 2H), 3.25 (m, 1H), 355 2.50 3.53 (m, 2H), 4.26 (m, 1H), 7.19 (d, 2H, J = 7.9Hz), 7.54 (d, 2H, J = 5.0 Hz ). 1F1 (CDCl3, 300 MHz): BDM_41789 382.43 g / mol N-0.8 (ppm) 1.25 (d, 6H, J = 6.9Hz), 1.69 (m, 2H), 1.94 (m, 2H), 2.43 (m, 4H), 2.89 (qp, 1H, J = 13.8 and 6.9Hz), 3.11 383 ND (s, 2H), 3.26 (m, 1H), 3.54 (m, 2H), 4.26 (m, 1H), 7.26 (d). , 2H, J = 8.2Hz), 7.56 (dt, 2H, J = 8.3 and 1.9Hz). 1F1 (CDCl3, 300 MHz): BDM_41793 396.46 g / mol 43 (ppm) 1.30 (s, 9H), 1.66 (m, 2H), 1.92 (m, 2H), 2.42 (m, 4H), 3.08 (s, 2H) ), 3.22 (m, 1H), 397 ND 3.50 (m, 2H), 4.24 (m, 1H), 7.38 (d, 2H, J = 8.6Hz), 7.54 (d, 2H, J = 8.6Hz).

BDM_41938 370.37 g / mol N-0 / 1H (CDCl3, 300 MHz):? (Ppm) 1.66 (m, 2H), 1.94 (m, 2H), 2.40 (m, 4H), 3.22 (s, 2H), 3.25 (m, 1H), 3.52 (m, 2H), 3.84 (s, 3H), 4.23 (m, 1H), 6.91 (m, 2H), 7.35 (td, 1H, J = 7.5 and 1.7Hz), 7.70 ( dd, 1H, J = 7.7 and 1.7 Hz). 371 0.02 1H (CD2Cl2, 300 MHz): BDM_43097 370.37 g / mol δ (ppm) 1.71 (m, 2H), 1.94 (m, 2H), 2.55 (m, 4H), 3.14 (s, 2H), 3.38 (m.p. , 1H), 3.58 (m, 2H), 371 0.29 3.85 (s, 3H), 4.17 (m, 1H), 6.99 (m, 1H), 7.21 (m, 2H), 7.35 (t, 1H, J = 7.8). Hz).

BDM_41935 1H (CDCl3, 300 MHz): δ (ppm) 1.68 (m, 2H), 1.94 (m, 2H), 2.46 (m, 4H), 3.09 (s, 2H), 3.25 (m, 1H), 3.53 ( m, 2H), 3.83 (s, 3H), 4.26 (m, 1H), 6.90 (m, 1H), 7.56 (m, 1H). 370.37 g / mol 16 371 ND 1H (CD2Cl2, 300 MHz): BDM_43116 400.40 g / mol 8 (ppm) 1.82 (m, 2H), 1.95 (m, 2H), 2.55 (m, 4H), 3.13 (s, 2H) ), 3.43 (m, 1H), 3.65 (m, 2H), 3.89 (s, 6H), 4.15 (m, 1H), 6.90 (d, 1H, J = 8.4Hz), 7.07 (dd, 1H, J = 8.3 and 2.0Hz), 7.35 (d, 1H, J = 1.9Hz). 401 ND BDM_41797 384.36 g / mol 1H (CDCl3, 300 MHz): δ (ppm) 1.69 (m, 2H), 1.95 (m, 2H), 2.48 (m, 4H), 3.08 (s, 2H), 3.25 (m. , 1H), 3.54 (m, 2H), 4.27 (m, 1H), 6.02 (s, 2H), 6.81 (d, 1H, J = 8.1Hz), 6.99 (dd, 1H, J = 8.1 and 1.7Hz) 7.27 (d, 1H, J = 1.5Hz). 1.30 (m, 2H), 1.94 (m, 2H), 2.45 (m, 4H), 3.10 (s, 2H), 3.24 (m, m.p. , 1H), 3.53 (m, 2H), 4.26 (m, 1H), 7.24 (m, 2H), 7.66 (dt, 2H, J = 9.0 and 2.7Hz). 425 <20H (CDCl3, 300MHz): BDM41931 374.79 g / mol at (ppm) 1.71 (m, 2H), 2.01 (m, 2H), 2.42 (m, 4H), 3.22 (s, 2H), 3.28 (m.p. m, 1H), 3.55 (m, 2H), 4.27 (m, 1H), 7.28 (m, 3H), 7.61 (dd, 1H, J = 7.3 and 1.9 Hz). 375 0.03 1H (CDCl3, 300 MHz): BDM41779 (ppm) 1.69 (m, 2H), 1.95 (m, 2H), 2.46 (m, 4H), 3.09 (s, 2H), 3.24 374.79 g / mol (m.p. , 1H), 3.53 (m, 2H), 375 5.80 4.26 (m, 1H), 7.35 (d, 2H, J = 13.2Hz), 7.53 (d, 2H, J = 13.5Hz). CI 1H (CDCl 3, 300 MHz): BDM_41783 358.34 g / mol 3 (ppm) 1.69 (m, 2H), 1.95 (m, 2H), 2.43 (m, 4H), 3.10 (s, 2H), 3.24 359, 0.50 (m.p. m, 1H), 3.53 (m, 2H), 4.27 (m, 1H), 7.05 (m, 2H), 7.60 (m, 2H). 1 H (CDCl 3, 300 MHz): BDM 41775 408.35 g / mol 8 (ppm) 1.72 (m, 2H), 1.97 (m, 2H), 2.47 (m, 4H), 3.15 (s, 2H), 3.27 (m, 1H). ), 3.55 (m, 2H), 409 0.40 4.28 (m, 1H), 7.52 (t, 1H, J = 7.7Hz), 7.66 (d, 1H, J = 7.8Hz), 7.85 (m, 1H).

BDM_41933 1H (CDCl3, 300 MHz):? (Ppm) 1.72 (m, 2H), 1.98 (m, 2H), 2.47 (m, 4H), 3.14 (s, 2H), 3.27 (m, 1H), 3.55 ( m, 2H), 4.29 (m, 1H), 7.66 (d, 1H, J = 8.3Hz), 7.75 (d, 1H, J = 8.2Hz). 408.35 g / mol 24 409 <20 BDM_43117 418.44 g / mol 1H (CD2Cl2, 300 MHz): δ (ppm) 1.74 (m, 2H), 1.95 (m, 2H), 2.45 (m, 4H), 3.07 (s, 3H), 3.17 (s, 2H), 3.34 (m, 1H), 3.54 (m, 2H), 4.15 (m, 1H), 7.84 (ddt, 2H, J = 8.7 and 2.0Hz), 7.96 (ddt, 2H). , J = 8.6 and 1.8 Hz). 419 ND 1H (CDCl 3, 300 MHz): BDM 41785 (ppm) 1.73 (m, 2H), 1.99 (m, 2H), 2.47 (m, 4H), 3.24 (s, 2H), 3.28 (m, 1H), 3.55 (m, 2H), 4.28 (m, 1H), 7.48 (m, 2H), 7.81 (m, 4H), 7.94 (m, 1H). 390.41 g / mol 26 391 ND Z ZO * 0 SSE. (FIS read) 17Z'L '(HI' w) Z017 '(HZ`s) 89. £' (Hz read) 17S. £ '(14I read) ## STR2 ## (H1) 17 (1) (HZ lu) LEI '(HZ lu) 17S'I (tudd) 2: (zHIAI 00 (ziDzCID) HI 800 £££. (HI read) OZ't '(HI lu)' (HI lu) LI. £ '(HI lu) SWZ' (HZ `s) 89'Z '(H-17 lu) 1717T' (H17 lu) ZLI` (H8 'tu) tc. T (wdd) 9: (71-11A1 00 IDCD) HI 800 L-17 £ (HI read) 6117 '(Hz read) S17. £' (HI read) 91. £ '(HZ `s) 99- Z '(1-1S) 17' 'Z' (H9 lu) 9L'I '(1-1 £ lu) .17S'i MIS read) 911 (tudd) 2: (zHIAI 00 £ IDCD) H1 Iou0 8 ## STR2 ## 1H (CDCl 3, 300 MHz): BDM 41777 330.31 g / mol δ (ppm) 1.68 (m, 2H), 1.93 (m.p. , 2.44 (m, 4H), 3.08 (s, 2H), 3.25 (m, 1H), 3.53 (m, 2H), 331 0.05 4.24 (m, 1H), 6.84 (m, 1H), 6.70 (b.p. dd, 1H, J = 3.4 and 0.6 Hz), 7.51 (m, 1H) 1 H (CDCl 3, 300 MHz): δ (ppm) 1.72 (m, 2H), 1.94 (m, 2H), 2.40 (m, 4H) ), 3.29 (s, 2H), 3.38 (m, 1H), 3.48 (m, 2H), 4.11 (m, 1H), 7.28 (m, 1H), 7.70 (td, 1H, J = 7.6 and 1.8 Hz) , 8.00 (dt , 1H, J = 8.0 and 1.1Hz), 8.58 (m, 1H). 341.34 g / mol N-0 342 0.15 1H (CD2Cl2, 300 MHz): BDM41418? (Ppm) 0.82 (d, 6H, J = 6.3 Hz), 1.36-1.45 (m, 2H), 1.56 (m, 1H) ), 1.71 (m, 2H), 1.87 (m, 2H), 315 5.00 3.02 (s, 2H), 3.27 (m, 1H), 3.42 (m, 2H), 3.95 (m, 1H), 7.33 (m, 3H), 7.55 (m, 2H). BDM_41796 1H (CDCl3): (ppm) 0.90 (d, 6H, J = 6.28Hz), 1.24 (m, 3H), 1.43 (m, 5H), 1.70 (m, 5H), 1.91 (m, 2H), 2.02. (m, 2H), 2.31 (m, 2H), 2.71 (m, 1H), 2.81 (m, 1H), 3.10 (m, 2H), 3.87 (m, 1H), 4.47 (m, 1H). 334 ND BDM_41788 1H (CDCl3): δ (ppm) 0.90 (d, 6H, J = 6.29Hz), 1.47 (m, 3H), 1.63 (m, 8H), 1.91 (m, 4H), 2.30 (m, 2H); ), 2.83 (m, 1H), 3.10 (m, 3H), 3.87 (m, 1H), 4.48 (m, 1H). 320 ND BDM_43118 1H (CD2Cl2): 3 (PPrn) 0.93 (d, 6H, J = 6.40Hz), 1.48 (m, 3H), 1.66 (m, 2H), 1.84 (m, 2H), 2.33 (m, 2H); ), 3.07 (s, 3H), 3.16 (s, 2H), 3.35 (m, 1H), 3.55 (m, 2H), 4.08 (m, 1H), 7.84 (ddt, 2H, J = 8.64Hz, J = 1.98Hz), 7.96 (ddt, 2H, J = 8.63Hz, J = 1.81Hz). 393 ND BDM_41780 1H (CDCl3): δ (ppm) Cl 0.89 (d, 6H, J = 6.26Hz), 1.47 (m, 3H), 1.62 (m, 2H), 1.91 (m, 2H), 2.30 (m, 2H), 3.06 (s, 2H), 3.25 (m, 1H), 3.50 (m, 2H), 4.19 (m, 1H), 7.33 (m, 2H), 7.53 (m, 2H). 349 ND BDM_41782 1H (CDCl3): δ (ppm) 0.93 (d, 6H, J = 6.28Hz), 1.51 (m, 3H), 1.25 (m, 2H), 1.94 (m, 2H), 2.31 (m, 2H); ), 2.39 (s, 3H), 3.11 (s, 2H), 3.29 (m, 1H), 3.54 (m, 2H), 4.21 (m, 1H), 7.21 (d, 2H, J = 7.97Hz), 7.54 (d, 2H, J = 8.14Hz). 329 ND BDM_41784 1H (CDCl3): δ (ppm) 0.90 (d, 6H, J = 6.28Hz), 1.48 (m, 3H), 1.64 (m, 2H), 1.92 (m, 2H), 2.32 (m, 2H). ), 3.08 (s, 2H), 3.26 (m, 1H), 3.52 (m, 2H), 4.20 (m, 1H), 7.06 (m, 2H), 7.60 (m, 2H). 333 ND BDM_41786 1H (CDCl3): δ (ppm) 0.91 (d, 6H, J = 6.27Hz), 1.49 (m, 3H), 1.64 (m, 2H), 1.95 (m, 2H), 2.33 (m, 2H); ), 3.22 (s, 2H), 365 ND 3.30 (m, 1H), 3.54 (m, 2H), 4.20 (m, 1H), 7.47 (m, 2H), 7.82 (m, 4H), 7.94 (m, 1H). 1H (CDCl 3):? (Ppm) 0.93 (d, 6H, J = 6.28Hz), 1.26 (d, 6H, J = 6.91Hz), 1.49 (m, 3H), 1.66 (m, 2H), 1.94 (m.p. m, 2H), 2.34 (m, 2H), 2.90 (qp, 1H, J = 13.79Hz, J = 6.90Hz), 3.11 (s, 2H), 3.29 (m, 1H), 3.54 (m, 2H), 4.23 (m, 1H), 7.27 (d, 2H, J = 8.21Hz), 7.58 (d, 2H, J = 8.32Hz). 1H (CDCl3): (ppm) 0.93 (d, 6H, J = 6.28Hz), 1.51 (m, 3H), 1.66 (m, 2H), 1.95 (m, 2H), 2.34 (m, 2H); , 3.11 (s, 2H), 3.28 (m, 1H), 3.54 (m, 2H), 4.25 (m, 1H), 7.28 (d, 2H, J = 7.98Hz), 7.67 (dt, 2H, J = 6.85). Hz, J = 2.02Hz). 399 ND BDM_41794 1H (CDCl3): (ppm) 0.91 (d, 6H, J = 6.27Hz), 1.32 (s, 9H), 1.48 (m, 3H), 1.62 (m, 2H), 1.92 (m, 2H) , 2.32 (m, 2H), 3.09 (s, 2H), 3.26 (m, 1H), 3.53 (m, 2H), 4.21 (m, 1H), 7.41 (d, 2H, J = 8.48Hz), 7.57 ( d, 2H, J = 8.40Hz). 371 ND BDM_41796 1H (CDCl3): (ppm) 0.88 (d, 6H, J = 6.30Hz), 1.23 (m, 5H), 1.45 (m, 6H), 1.69 (m, 6H), 2.28, 321, ND (m, 3H), 2.64 (s, 2H), 3.17 (m, 1H), 3.43 (m, 2H), 4.13 (m, 1H). BDM_41798 1H (CDCl3): (ppm) 0.93 (d, 6H, J = 6.30Hz), 1.49 (m, 2H), 1.66 (m, 2H), 1.78 (m, 2H), 1.94 (m, 2H), 2.34 (m, 2H), 3.07 (s, 2H), 3.27 (m, 1H), 3.54 (m, 2H), 4.22 359 ND (m, 1H), 6.02 (s, 2H), 6.81 (d, 1H, J); = 8.30Hz), 6.99 (dd, 1H, J = 8.06Hz, J = 1.70Hz), 7.28 (d, 1H, J = 1.64Hz).

BDM41799 1H (CDCl3): δ (ppm) 0.91 (d, 6H, J = 6.29Hz), 1.48 (m, 3H), 1.64 (m, 2H), 1.93 (m, 2H), 2.33 (m, 2H), 3.28 (s, 2H), 3.42 (m, 1H), 3.59 (m, 2H), 4.04 (m, 1H), 7.27 (m, 1H), 7.70 (td, 1H, J = 7.67Hz, J = 1.77Hz). ), 8.00 (dt, 1H, J = 7.99Hz, J = 1.03Hz), 8.58 (m, 1H). 316 1.30 BDM_41932 1H (CDCl3): δ (ppm) 0.92 (d, 6H, J = 6.29Hz), 1.49 (m, 3H), 1.65 (m, 2H), 1.98 (m, 2H), 2.33 (m, 2H). ), 3.27 (s, 2H), 3.30 (m, 1H), 3.54 (m, 2H), 4.19 (m, 1H), 7.27 (m, 3H), 7.61 (dd, 1H, J = 7.29Hz, J = 1.81Hz). 349 1.30 BDM_41934 1H (CDCl3): (ppm) 0.90 (d, 6H, J = 6.26Hz), 1.48 (m, 3H), 1.70 (m, 2H), 1.93 (m, 2H), 2.31 (m, 2H). , 3.10 (s, 2H), 3.26 (m, 1H), 3.49 (m, 2H), 4.21 (m, 1H), 7.63 (d, 1H, J = 8.29Hz), 7.73 (d, 1H, J = 8.24). Hz). 383 ND BDM_41936 1H (CDCl3): 3 (ppm) 0.90 (d, 6H, J = 6.26Hz), 1.48 (m, 3H), 1.61 (m, 2H), 1.91 (m, 2H), 2.31 (m, 2H); ), 3.07 (s, 2H), 345 ND 3.26 (m, 1H), 3.51 (m, 2H), 3.82 (s, 3H), 4.19 (m, 1H), 6.89 (m, 1H), 7.55 (m, 1H).

BDM_41939 1F1 (CDCl3): (ppm) 0.91 (d, 6H, J = 6.30Hz), 1.48 (m, 3H), 1.62 (m, 2H), 1.92 (m, 2H), 2.32 (m, 2H), 3.22 (s, 2H), 3.27 (m, 1H), 3.57 (m, 2H), 3.85 (s, 3H), 4.18 (m, 1H), 6.92 (m, 2H), 7.35 (td, 1H, J = 7.46). Hz, J = 1.74Hz), 7.70 (dd, 1H, J = 7.68Hz, J = 1.72Hz). 345 0.63 BDM_43103 1F1 (CD2Cl2): δ (pPm) 1.72 (m, 2H), 1.86 (m, 4H), 2.15 (m, 2H), 2.43 (m, 2H), 3.29 (s, 2H), 3.34 (m. , 1H), 3.52 (m, 389 0.77 2H), 4.10 (m, 1H), 7.33 (m, 2H), 7.46 (m, 1H), 7.61 (m, 1H). 1H (MeO D): δ (ppm) 1.74 (m, 6H), 2.13 (m, 2H), 2.52 (t, 2H, J = 7.20Hz), 3.26 (s, 2H), 3.40 (m, 1H); , 3.49 (m, 1H), 3.65 (m, 1H), 3.99 (m, 1H), 7.40 (m, 3H), 7.65 (m, 2H). 1.75 (m, 2H), 1.86 (m, 4H), 2.15 (m, 2H), 2.42 (m, 2H), 3.07 (s, 3H), 3.16 (m.p. s, 2H), 3.34 (m, 1H), 3.52 (m, 2H), 4.11 (m, 1H), 7.85 (ddt, 2H, J = 8.65Hz, J = 1.94Hz), 7.97 (ddt, 2H, J); = 8.65Hz, J = 1.72Hz). 433 <20 BDM_43092 1H (CD2Cl2): 8 (Pen) 1.72 (m, 2H), 1.94 (m, 2H), 3.14 (s, 2H), 3.35 (m, 1H), 3.59 (m, 1H), 3.67 ( m, 1H), 4.13 (m, 351 <20H), 4.73 (d, 1H, J = 3.80Hz), 6.95 (m, 3H), 7.30 (m, 2H), 7.42 (m, 3H), 7.46 ( m, 2H). BDM-43113 (CD2Cl2): δ (MPm) 1.76 (m, 1H), 1.85 (m, 3H), 3.13 (s, 3H), 3.16 (s, 2H), 3.31 (m, 1H), 3.62 (m, 1H); ), 3.76 (m, 1H), 4.05 (m, 2H), 4.27 (m, 1H), 7.42 (m, 3H), 7.64 (m, 2H). 337 <20 BDM-43114 1 H (CD2Cl2): δ (PPin) 1.49 (m, 1H), 1.69 (m, 2H), 1.89 (m, 1H), 3.03 (d, 2H, J = 3.90Hz), 3.36 (m, 1H), 3.52 (m, 2H), 335 <20 4.10 (m, 1H), 7.25 (m, 3H), 7.33 (m, 2H), 7.41 (m, 3H), 7.63 (m, 2H).

1H (CD2Cl2):? (PPm) 1.09 (m, 3H), 1.52 (m, 10H), 2.18 (m, 1H), 2.37 (m, 2H), 3.14 (s, 2H), 327 <? m, 1H), 3.54 (m, 2H), 4.04 (m, 1H), 7.41 (m, 3H), 7.64 (m, 2H). BDM_43102 1H (CD2Cl2): δ (MPm) 1.42 (m, 1H), 1.72 (m, 2H), 1.91 (m, 2H), 2.11 (m, 1H), 2.23 (m, 5H), 3.15 (s, 2H); ), 3.37 (m, 1H), 3.54 (m, 2H), 4.09 (m, 1H), 5.72 (m, 1H), 5.78 (m, 1H), 7.42 (m, 3H), 7.65 (m, 2H); . 325 <20 BDM_43259 1H (CD2Cl2): (PPm) 58 1.59 (m, 2H), 1.87 (m, 2H), 3.11 (s, 2H), 3.35 (m, 1H), 3.57 (m, 2H), 3.94 ( d, 2H, J = 2.40Hz), 4.13 (m, 1H), 6.92 (m, 1H), 6.97 (dd, 1H, J = 5.12Hz, J = 3.47Hz), 7.24 (dd, 1H, J = 5.20; Hz, J = 1.14Hz), 7.41 (m, 3H), 7.64 (m, 2H). 341 <20 BDM_43104 1F1 (CD2Cl2): 8 (PPm) 1.54 (m, 1H), 1.69 (m, 1H), 2.65 (m, 2H), 2.92 (m, 2H), 3.11 (s, 2H), 3.33 ( m, 1H), 3.48 (m, 2H), 4.10 (m, 1H), 7.20 (m, 5H), 7.35 (m, 3H), 7.64 (m, 2H). 59 349 1.00 As an example of measured solubility, the compound 10 (BDM41420) has a solubility equal to 150 μM measured according to the abovementioned protocol.

Claims (14)

1. A spiroisoxaline type compound of general formula (1): 0, R1 112 R2 (I) wherein: m = 0 or 1; n = 0 or 1; R 1 represents a group chosen from the following groups: linear or branched C1-C5 alkyl chains, linear or branched and substituted C1-C5 alkyl chains, in particular substituted by at least one fluorine (F) atom, in particular linear or branched C1-C3 alkyl chains substituted with at least one fluorine atom (F) or with a saturated or unsaturated C3-C6 cyclic group, saturated or unsaturated C3-C6 cyclic groups and CN groups, CH 2 CN and CH 2 NC 3, optionally substituted phenyl, in particular phenyl substituted with a Cl or F atom, optionally substituted benzyl, in particular benzyl substituted with a Cl or F atom, 0-phenyl and thiophenyl; R2 is chosen from the following groups: phenyl, benzyl, naphatalenyl, substituted phenyl, in particular phenyl substituted with at least one linear or branched C1-C4 alkyl chain, phenyl substituted with at least one C1-C4 alkyl chain, linear or branched and substituted, in particular substituted by at least one fluorine atom (F), phenyl substituted with a group selected from OCH3, OCF3, CL F, CH3SO2 and CF3, a phenyl group of which two consecutive carbon atoms are substituted by a same group O-CH 2 -O, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and heterocycles having 5 or 6 vertices, saturated or unsaturated having at least one atom selected from S, N and O in the ring, in particular aromatic heterocycles. at 5 or 6 vertices comprising at least one atom chosen from S, N and O in the ring. 2. Compound according to claim 1, characterized in that m = n = 1. 3. Compound according to claim 1 or 2, characterized in that RI is chosen from the following groups: -CH2CF3, -CF2CF3, - (CH2) 2CF3, -CT12-isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, -CH2- cyclopropyl, -C1H2cyclobutyl, CH2cyclopentyl, optionally substituted phenyl, in particular phenyl substituted with Cl or F, optionally substituted benzyl, in particular benzyl substituted by Cl or F, O-phenyl and thiophenyl. 4. Compound according to any one of claims 1 to 3, characterized in that R1 is selected from -CH2CF3 and - (CH2) 2CF3. 5. Compound according to any one of the preceding claims, characterized in that R2 is chosen from the following groups: phenyl, ortho-substituted phenyl groups by OCH3, OCF3, Cl, F or CF3, in particular substituted by OCH3 or Cl . 6. Compound according to any one of claims I to 4, characterized in that R2 is chosen from aromatic heterocycles with 5 or 6 vertices which comprise at least one atom selected from the atoms S, N and O adjacent to the atom. of the carbon-bonded heterocycle at the N of the ring of the formula (I). 7. Compound according to claim 5, characterized in that R2 is chosen from the following groups: 8. Compound according to any one of claims 1 to 4, characterized in that R2 is chosen from the following groups: NI 22 i * N and 9. Compound according to claim 1 characterized in that it is selected from the following compounds: N-O N-O S, S N N-O 49 -n-n -n -n 10. Compounds according to any one of claims 1 to 9 for their use as a medicament. .5>; ,; N-0,; ; e; 51 11. Compounds according to any one of claims 1 to 9 for their use in the treatment of bacterial and fungal infections, especially in the treatment of tuberculosis, leprosy or atypical mycobacterioses. 12. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims I to 9 and a pharmaceutically acceptable excipient. 13. A composition according to claim 12, characterized in that it further comprises, as active ingredient, at least one antibiotic active against bacteria and / or mycobacteria, in particular chosen from the antibiotics activated by the enzymatic pathway. the EthA. 14. Product containing at least one compound according to any one of claims 1 to 9 and at least one antibiotic active against bacteria and / or mycobacteria and in particular selected from the antibiotics activatable by the enzymatic pathway of the EthA, in particular an antibiotic selected from ethionamide, prothionamide, isoxyl and thiacetazone, as a combination product in antituberculous, anti-lepromatous or general anti-mycobacterin therapy. 20 52